Effect of intravenous immunoglobulin on mortality in hospitalized patients with COVID‐19: A systematic review and meta‐analysis of randomized controlled trials

Abstract Background and Aims We performed a meta‐analysis of randomized controlled trials (RCTs) to summarize the overall effect of intravenous immunoglobulin (IVIG) on mortality outcomes among hospitalized coronavirus disease 2019 (COVID‐19) patients. Methods We systematically searched electronic databases up to June 1, 2023. Pooled odds ratio (OR) of mortality with a 95% confidence interval (CI) was generated using a random‐effects model. The risk of bias was appraised using the Cochrane risk‐of‐bias Version 2 tool for randomized trials. Results Nine RCTs were included: three RCTs had an overall low risk of bias, four RCTs had some concerns in the overall risk of bias, and two RCTs trials had an overall high risk of bias. The use of IVIG indicated a significant reduction in the odds of mortality (pooled OR = 0.69; 95% CI 0.50–0.96) relative to nonuse of IVIG. Subgroup analysis in patients with a severe course of COVID‐19 revealed no significant reduction in the odds of mortality (pooled OR = 0.58; 95% CI 0.29–1.16). Conclusions We suggest exercising caution when interpreting effectiveness of IVIG in reducing mortality among hospitalized patients with COVID‐19. Our findings emphasize for larger trials with rigorous study designs to better understand the impact of IVIG, particularly in those with severe COVID‐19.

Intravenous immune globulin (IVIG) is a blood product derived from the pooled serum or plasma of thousands of healthy paid donors.The primary component of IVIG is the serum IgG fraction, mainly consisting of the IgG1 and IgG2 subclasses. 1 Therefore, the administration of IVIG in the context of immunodeficiency states could provide passive immunity with adequate concentrations of antibodies against a broad range of pathogens.Nevertheless, the decision to repurpose IVIG for the treatment of coronavirus disease 2019 (COVID- 19) is based on its several potential anti-inflammatory and immunomodulatory effects, [2][3][4] since we have currently acknowledged that hyperactive immune response can occur in a certain fraction of patients with COVID-19. 5sitive outcomes have been observed using IVIG in clinical studies involving COVID-19 patients.A recent systematic review and meta-analysis by Xiang et al. 6 examined the efficacy of IVIG in treating COVID-19 patients.This meta-analysis, which included seven clinical studies (three observational), found that IVIG administration was associated with significant mortality benefits compared to control treatment (pooled risk ratio = 0.67; 95% confidence interval [CI] 0.52−0.86).
Nevertheless, a meta-analysis of observational studies, especially with a retrospective design, could introduce bias since the efficacy estimates may not be adjusted with important confounders.
Therefore, the reported mortality benefits of IVIG in COVID-19 patients should be interpreted with caution.Several randomized controlled trials (RCTs) have assessed the impact of IVIG on mortality outcomes in COVID-19 patients.Our objective was to conduct a systematic review and meta-analysis to summarize its effect based on randomized evidence.

| METHODS
This study followed the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRIS-MA). 7We conducted a systematic search of electronic databases, including PubMed, Scopus, and the Cochrane Central Register of Controlled Trials, as well as preprint repositories (medRxiv and SSRN), from their inception until June 1, 2023.The search included the following keywords and their MeSH terms: "COVID-19," "SARS-CoV-2," "novel coronavirus disease," "intravenous immunoglobulin," "intravenous immune globulin," "IVIG," "immunotherapy," "randomized," "controlled trial," and "clinical trial."Additionally, we searched the United States Clinical Trial Registries (clinicaltrials.gov)for ongoing registered clinical trials of IVIG in the treatment of COVID-19 that had released findings.Additionally, we manually examined the reference lists of relevant articles to identify further studies.
Our inclusion criteria focused on RCTs that compared the mortality outcomes of IVIG with those of comparators in hospitalized COVID-19 patients.We excluded single-arm trials, non-randomized trials, and trials that did not report mortality events.The primary outcome of interest was all-cause mortality.
Two authors (C. S. K. and D. S. R.) independently assessed each included trial, extracting key study characteristics using a predesigned data extraction form.The extracted data encompassed the first author's surname, the design of the trial, the country where the study was conducted, the age of the participants, the proportion of patients requiring respiratory support at baseline, the IVIG regimen, comparative agents, and mortality events.The risk of bias in the included trials was assessed by two authors (C. S. K. and S. S. H.) using Version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2). 8This tool evaluates potential bias across several domains, including randomization, deviations from intervention, missing outcome data, measurement of outcomes, and selection of reported results.Each domain was judged as "Low," "High," or "Some concerns" for risk of bias.An overall low risk of bias indicated high methodological quality, some concerns indicated potential issues in one or more domains, and a high risk of bias indicated significant methodological deficiencies that might affect the reliability of the results.
For the meta-analysis, we used a random-effects model to pool mortality estimates from individual trials, presenting the results as pooled odds ratios (OR) with 95% confidence intervals (CIs).We assessed heterogeneity using I² statistics and the χ² test, with thresholds for statistical significance set at 50% and p < 0.10, respectively.To ensure the robustness of our findings, we performed a sensitivity analysis by systematically excluding trials with a high risk of bias.This analysis aimed to determine if the main results were consistent when higher-risk studies were removed.Additionally, we conducted a subgroup analysis to explore the effect of IVIG on mortality within specific subpopulations, particularly focusing on trials that included only hospitalized patients with severe COVID-19.This subgroup analysis aimed to identify whether the mortality benefits of IVIG were more pronounced in this subset of patients.All analyses were conducted using Meta XL, version 5.3 (EpiGear International).
The study selection process and review flowchart are illustrated in Figure 1.

Key points
• The use of intravenous immunoglobulin (IVIG) indicated a significant reduction in the odds of mortality relative to nonuse of IVIG.
• Subgroup analysis in patients with a severe course of coronavirus disease 2019 (COVID-19) revealed no significant reduction in the odds of mortality.
• We suggest exercising caution when interpreting the efficacy of IVIG in reducing mortality among hospitalized patients with COVID-19.
INSIGHT 013, spanning 63 sites in 11 countries. 17Table 1 provides details of these studies.
Sakoulas et al. 11 used 0.5 g/kg once daily for 3 days.Tabarsi et al. 12 and Raman et al. 10 administered 0.4 g/kg once daily for 3 and 5 days, respectively.Ali et al. 13 administered one of four dosages (0.15, 0.2, 0.25, and 0.3 g/kg) as a single dose.Parikh et al. 14 15 INSIGHT 013, 17 and Maor et al. 16 had a low risk of bias across all domains.Four trials had some concerns regarding bias: Sakoulas et al. 11 had unclear allocation concealment and an open-label design; Tabarsi et al. 12

had unclear allocation
concealment, an open-label design, and lacked a trial protocol/ statistical analysis plan; Raman et al. 10 had an open-label design and lacked a trial protocol/statistical analysis plan; Ali et al. 13 had unblinded personnel/carers.Two trials had a high risk of bias: Gharebaghi et al. 9 had missing outcome data and unclear randomization details, and Parikh et al. 14 had baseline biomarker differences and an open-label design.
The meta-analysis of the nine trials 9-17 revealed a significant reduction in the odds of mortality among hospitalized COVID-19 patients receiving IVIG compared to the control group (Figure 2; pooled OR = 0.69; 95% CI 0.50−0.96),providing sufficient evidence to reject the null hypothesis of no significant difference.Sensitivity analysis, excluding trials with a high risk of bias, showed no significant mortality reduction (pooled OR = 0.75; 95% CI 0.53−1.05).Similarly, a subgroup analysis of trials 9,[11][12][13]15 involving only hospitalized patients with severe COVID-19 did not show significant mortality T A B L E 2 Risk of bias of included trials.

| DISCUSSION
To the best of the authors' knowledge, this is the most current systematic review and meta-analysis of RCTs investigating the effect of IVIG on mortality outcomes in COVID-19 patients.Our metaanalysis, which focuses on RCTs-the gold standard for assessing causal relationships between interventions and outcomesdemonstrates that IVIG administration significantly reduced the risk of mortality in hospitalized COVID-19 patients.
Our findings concur with real-world observations.Shao et al., 18 in their multicentre retrospective cohort study, which investigated the efficacy of IVIG (0.1−0.One aspect that requires attention is the impact of IVIG on specific patient populations, particularly those with severe COVID-19.
The subgroup analysis conducted on trials 9,[11][12][13]15 which focused on hospitalized patients with severe COVID-19, did not demonstrate significant mortality benefits associated with IVIG administration relative to nonuse of IVIG. Neertheless, it should be noted that the definition of severe illness differs across the included trials, which makes it challenging to draw definitive conclusions regarding the efficacy of IVIG in this specific patient population.Within the existing trials, there is an individual analysis worth considering.The trial reported by Gharebaghi et al. 9 that recruited patients with severe COVID-19, defined as those with oxygen saturation levels below 90%, observed a significant reduction in mortality with IVIG administration.
This finding suggests that IVIG might be more effective in patients with a specific severity criterion, such as low oxygen saturation levels.
5 g/kg/day for the duration of 5−15 days) in 325 severely and critically ill hospitalized patients with COVID-19, reported that that the administration of IVIG is associated with mortality benefits (hazard ratio = 0.40; 95% CI 0.20−0.80) in hospitalized patients critically ill with COVID-19.In addition, in a single-center retrospective cohort study by Esen et al.,19 involving 93 hospitalized patients with severe COVID-19, it was reported that IVIG treatment was associated with a significantly prolonged median survival time (68 days compared to 18 days; p = 0.014).Although observational studies are notoriously associated with biases, which may question the implications of their findings, our meta-analysis of RCTs resulted in robust conclusions which support these findings.Our study has important implications in the management of hospitalized COVID-19 patients globally.The use of IVIG has been associated with beneficial outcomes and we confirm the mortality reduction among hospitalized patients with COVID-19 treated with IVIG.The mechanisms behind the clinical benefits of IVIG are not fully understood.However, IVIG has the potential to mitigate cytokine storms in COVID-19 patients by scavenging complements, inhibiting innate immune cells and effector T-cell activation, and expanding regulatory T cells, which is evident in the reduction in the inflammatory mediators following IVIG therapy 18 ; the trial by Ali et al. 13 showed that the decrement in C-reactive protein level in the intervention arm (45.5−87.4mg/L) was more than that of the control arm (18.3 mg/L) after 24 h of IVIG therapy; and the trial by Sakoulas et al. 11 demonstrated that IVIG therapy reduced interleukin-6 serum concentrations, with the IVIG group showing a median of 5 pg/mL compared to the control group's median of 18 pg/mL after 24−48 h of treatment.Therefore, future trials could target only hospitalized patients with COVID-19 and biochemical evidence of inflammation to demonstrate mortality benefits.
These results highlight the importance of conducting further randomized trials to address the gap in knowledge regarding the efficacy of IVIG in patients with severe COVID-19.Standardizing the definition of severe illness across trials would enable more reliable comparisons and conclusions.Adverse reactions to IVIG are a concern since they are reported to affect up to 50% of patients receiving IVIG before the COVID-19 F I G U R E 2 Forest plot showing the pooled odds ratio of mortality among hospitalized patients with COVID-19 treated with IVIG compared to those not treated with IVIG.COVID-19, coronavirus disease 2019; IVIG, intravenous immunoglobulin.

1
Study characteristics of included trials. 14